Neuroinflammation mainly involves the presence and activation, in neural tissue, of two types of immune cells: microglia (Stoll & Jander, 1999) and leukocytes (Man et al., 2007), causing local release of immune mediators. Microglial cells are resident cells of the central nervous system (CNS) (Kreutzberg, 1996), which participate in its immune surveillance and defence. They are activated under pathological conditions and acquire functions that finally lead to degeneration processes by damaging or killing neurons (Tilleux & Hermans, 2007). Leukocytes are located throughout the body, including the blood and lymphatic system. Under physiological condition, only small numbers of leukocytes such as T lymphocytes are present in CNS parenchyma. Their passage is limited by the blood-brain-barrier (BBB) (Wekerle et al., 1986; Hickey et al., 1991; Carvey et al., 2005), which is a hermetic barrier made of endothelial cells that controls the access of blood stream elements to the CNS (Rubin & Staddon, 1999; Prat et al., 2001). Under pathological condition, hematogenous leukocytes readily leave blood stream and reach the parenchyma to participate to a destructive inflammatory response (Man et al., 2007; Cardona et al., 2008), since it has been shown that BBB integrity is impaired during inflammation (Lossinsky & Shivers, 2004).
Neuroinflammation has been proposed to be implicated in the progressive nature of neurodegenerative diseases (Block & Hong, 2005). Involvement of neuroinflammation is for example well-known in neurological disorders, such as Multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Acute disseminated encephalomyelitis (ADEM) and Neuromyelitis optica (NMO).
Precise pathogenesis of AD remains unclear. However, it has been hypothesized that AD is manifested by BBB impairment and neuroinflammation. Indeed, an increased number of Ig (Ishii & Haga, 1976; Mann et al., 1982; Licandro et al., 1983) has been found in the brain parenchyma, as well as CD4 or CD8 T cells (Itagaki et al., 1988; Rogers et al., 1988; McGeer et al., 1989; Singh, 1997; Neumann, 2001) in the hippocampus and temporal cortex of AD patients. Major histocompatibility complex (MHC) class I and II molecules, involved in antigen presentation and binding to T cells have also been identified in areas showing hallmark pathology (Itagaki et al., 1988; Rogers et al., 1988; McGeer et al., 1989; Mattiace et al., 1990; Perlmutter et al., 1992; Gonzalez-Scarano & Baltuch, 1999; Szpak et al., 2001; Kim & de Vellis, 2005; Walker & Lue, 2005).
PD is another neurodegenerative disorder of unknown aetiology. BBB impairment has been hypothesized as a causative mechanism in PD (Kortekaas et al., 2005). It has been suggested that under inflammatory state, VCAM-1 and ICAM-1 receptors are upregulated, due to microglial release of proinflammatory cytokines (Neumann & Wekerle, 1998). This upregulation results in recruitment of T cells and monocytes that harbor the several adequate counter receptors (CD11a/CD18 (LFA-1) and very late antigen-4) (Neumann & Wekerle, 1998).
Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the CNS. It is a monophasic disease that can arise spontaneously. However, 5 to 25% of patients experience relapse (Marchioni et al., 2005; Tenembaum et al., 2002) with recurrent or multiphasic forms. Most important symptoms include fever, headache, drowsiness, seizures and coma. The mortality rate can reach 5% (Menge et al., 2007). The exact aetiology of ADEM is at present unknown. It is characterized by a widespread of demyelination in the white matter of the brain and spinal cord. It can also involve the cortex and deep gray matter structures. From a histological point of view, ADEM is characterized by perivenular infiltrates of T cells and macrophages, associated with demyelination. Axonal damage has also been identified in the brains of some patients (DeLuca et al., 2004; Ghosh et al., 2004). It has been suggested that ADEM may result of the activation of myelin-reactive T cell clones involved in a nonspecific inflammatory process (Tenembaum et al., 2007). ADEM is compared to multiple sclerosis, since it involves autoimmune demyelination (Rust, 2000; Poser, 2008). No standard therapy exists for ADEM since results are generally obtained from case reports and small series. Treatments usually comprise nonspecific immunosuppressant therapy, such as steroids, immunoglobulin, or plasma exchange, which are used in other autoimmune diseases including MS (Tenembaum et al., 2007).
Neuromyelitis optica (NMO) is an infrequent autoimmune, inflammatory and demyelinating disease of the CNS that affects myelin of the neurons placed at the optic nerves and spinal cord. The disease can be either monophasic or relapsing (Ghezzi et al., 2004). Extensive inflammation of the optic nerve (optic neuritis) and spinal cord (myelitis) usually leads to severe, permanent, relapse-related neurologic impairment (e.g., blindness, paraplegia) within 5 years (Wingerchuk & Weinshenker, 2003). Hallmarks of NMO are inflammatory lesions, cavitation, necrosis and axonal pathology. They have been observed in both grey and white matter of the spinal cord and optic nerves (Lucchinetti et al., 2002). At disease onset, the brain parenchyma is normal or may demonstrate few nonspecific subcortical white matter changes. It has been suggested that asymptomatic brain lesions are frequent in NMO at a later stage of the disease (Pittock et al., 2006). Until recently, NMO was considered to be a variant of multiple sclerosis. However, clinical, neuroimaging, laboratory and pathological characteristics differ. For example, NMO attacks are not mediated by T cells but rather by B cells in an autoimmune manner (Lucchinetti et al., 2002). There is at the moment no established optimal treatment for NMO since no randomized controlled trials have been performed. At present, parenteral corticosteroids are widely employed as first-line treatment of optic neuritis and myelitis attacks (Mandler et al., 1998), whereas therapeutic plasmapheresis that aims at removing autoantibodies, immune complexes and inflammatory mediators from the plasma, is applied in the case of corticosteroids failure (Keegan et al., 2002; Lehmann et al., 2006).
Multiple sclerosis is considered as an inflammatory demyelinating disease of the CNS (Skaper, 2007; Lassmann et al., 2007). For 85% of patients, disease course begins with a phase of recurrent and reversible neurological troubles termed Relapsing-Remitting MS (RRMS). This condition appears by the third-fourth decade of life. It can last for years and decades, with alternate phases of attacks with relapses, during which the patients recuperate neurological function (Trapp & Nave, 2008). Attacks last from a few days to weeks, and remissions a few months to years. After 8 to 20 years, patients enter the Secondary Progressive MS (SPMS) that is characterized by a continuous and irreversible neurological decline. A rarer disease form named Primary Progressive MS (PPMS) affects 15% of MS patients. There are no relapses occurring in PPMS disease form and disease is progressive from the onset. It occurs later than RRMS form (39 vs 29 years). Fifty percent of MS patients are unable to perform household and employment responsibilities 10 years after disease onset, and 50% are nonambulatory 25 years after disease onset (Trapp & Nave, 2008). Morphological alterations in CNS anatomy lead to paralysis, sensory disturbances, lack of coordination, and visual impairment among the most common features. These alterations (detected by magnetic resonance imaging (MRI), histopathologic evaluations and disease course vary significantly among patients (Agrawal & Yong, 2007).
Multiple sclerosis (MS) is the most frequent non traumatic neurological disease among young adults in North America and Europe, with 3.6 and 2.0 cases per 100 000 person-years incidence for women and men respectively (Alonso & Hernan, 2008). Multiple factors such as genetics, environment and infectious agents are part of MS development. It is considered as a non-herited disease. However, one can inherit a greater susceptibility to acquiring MS and it has been proposed that MS is a complex disease involving multiple genes with a low penetrance (Olsson & Hillert, 2008). Increased risk of developing MS has also been associated with the major histocompatibility complex (MHC) class II (Trapp & Nave, 2008), including the HLA-DRB1 gene which accounts for 16 to 60% of the genetic susceptibility (Haines et al., 1998). This supports the involvement of immune system in MS physiopathology. Additional susceptibility genes have been associated with MS, such as Interleukin-7 and -2 receptor alpha chain that display a low odds ratio of 1.3 (Olsson & Hillert, 2008). Inflammation, breakdown of BBB, demyelination, and axonal transection are pathological features of acute MS lesions. In RRMS phase, disability is caused by focal areas of inflammation where myelin, oligodendrocytes (responsible of myelin formation) and axons are destroyed (Ganter et al., 1999; Bjartmar et al., 2000; Lovas et al., 2000; Trapp et al., 1998). Attention is primarily focused on demyelinated lesions in the white matter at the chronic stage of the disease. However, evidence has accumulated that large areas of grey matter are also affected in MS patients (Stadelmann et al., 2008). It has been shown that T cells (mainly MHC-class I restricted CD8+ T cells) participate actively to inflammation, in addition to activated microglia (Lassmann et al., 2007). Moreover, impairment of BBB has been observed (Hochmeister et al., 2006; Kirk et al., 2003), allowing T cells to enter CNS. Relapse lasts a few month and the patients recuperate neurological function, due to resolution of inflammation and remyelination (Trapp et al., 1998; Ferguson et al., 1997). Transition toward SPMS and PPMS stages occurs when CNS can no longer compensate for additional neuronal loss (Trapp et al., 1999). In SPMS and PPMS stages, focal demyelinated white matter lesions remain, but new inflammatory active demyelinating lesions are infrequent. The pre-existing active lesions expand slowly, showing a little myelin breakdown activity especially in margins. These lesions show moderate inflammatory infiltrates, principally composed of T cells (CD8+ T cells) and active microglia (Prineas et al., 2001). In addition, diffuse atrophy of the grey and white matter as well as ‘normal-appearing white matter’ (NAWM) are observed (Miller et al., 2002).
Disease mechanisms pertinent to neuroinflammation have often been inferred from the Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. This model is induced by sensitization of animals with brain tissue, myelin or protein antigens or by passive transfer of autoreactive T cells (Lassmann, 2008). Animals develop an inflammatory demyelinating disease that closely looks like MS (Lassmann, 2008). This model also supports the hypothesis according to which MS is an autoimmune disease. Indeed immunological data show autoreactive T cells and autoantibodies in circulation and in the cerebrospinal fluid. Since inflammation is a main hallmark of acute MS lesions, aggressive anti-inflammatory strategies have been assessed during RRMS, performing neuroprotective effects. Interferon β (IFNβ) and glatiramer acetate (GA) are commonly used to treat RRMS. IFNβ inflammatory effects concern decrease of antigen presentation, apoptosis, and entry of immune cells into the CNS (Neuhaus et al., 2005). GA mimics myelin basic protein (MBP), a major component of CNS myelin. It reduces antigen presentation and stimulates T cell secretion of cytokines associated with anti-inflammatory or lymphocytes T helper 2 actions (Neuhaus et al., 2001). Natalizumab, a humanized monoclonal antibody specific for α4 integrins, has also been proposed for the treatment of RRMS (Polman et al., 2006; O'Connor et al., 2004). Another study suggests a role of recombinant erythropoietin as a protective agent in MS, but numerous problems are associated with this strategy since the use of erythropoietin and erythropoietin-analogues leads to simultaneous targeting of both the erythropoietic and tissue-protective properties of erythropoietin (Konstantinopoulos et al., 2007).
There exists a need for efficient therapies for treating neuroinflammation. There is also a strong need in the art for novel and effective therapies for the treatment of diseases having a neuroinflammatory component, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Acute disseminated encephalomyelitis and Neuromyelitis optica.